Compounds which selectively modulate the CB2 receptor

ABSTRACT

Compounds of formula (I) 
                         
are disclosed. Compounds according to the invention bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.

APPLICATION DATA

This application claims benefit to U.S. provisional application Ser. No.61/186,920 filed Jun. 15, 2009.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to novel compounds which modulate the CB2receptor and their use as medicaments.

2. Background Information

WO2008014199, WO2008039645 discuss the CB2 receptor, and the therapeuticuses of the CB2 receptor agonist compounds disclosed therein. It isbelieved that the highly selective activation of the CB2 receptor withan agonist may offer avenues of harnessing the beneficial effects whileavoiding the adverse effects seen with dual CB1/CB2 cannabinoid receptoragonists (see e.g. Expert Opinion on Investigational Drugs (2005),14(6), 695-703). It is desirable therefore to provide agonists of CB2with minimized CB1 activity.

PCT Application Number PCT/US09/34464 discloses compounds having CB2agonist activity. The compounds of the present invention differstructurally from the above disclosed compounds, for example the presentR5 in the formula (I) disclosed hereinbelow. Additionally, the compoundsof the present invention have lower CB1 activity than the compoundsdisclosed in the cited art.

BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compounds which bind to andmodulate the CB2 receptor and have lower CB1 receptor activity. Theinvention also provides methods and pharmaceutical compositions fortreating inflammation by way of the administration of therapeuticamounts of the compounds of the invention. Lastly, the inventionprovides a method and pharmaceutical compositions for treating pain byway of the administration of therapeutic amounts of the compounds of theinvention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Flow rate graph time vs % organic (B) using evaporative lightscattering detectors.

FIG. 2: Flow rate graph time vs % organic (B) using HPLC-MS equipment.

DETAILED DESCRIPTION OF THE INVENTION

In the broadest generic embodiment 1, the invention provides compoundsof the formula

wherein:

-   ring A is a 5-membered heteroaryl ring;-   R¹ is hydrogen, C₁₋₁₀ alkyl or C₃₋₁₀ cycloalkyl which is optionally    substituted with 1-3 C₁₋₁₀ alkyl, each R¹ or it's substituent is    optionally halogenated;-   R² is C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, arylsulfonyl, arylcarbonyl,    C₁₋₁₀ acyl, C₃₋₁₀ cycloalkylcarbonyl, heterocyclylcarbonyl,    heteroarylcarbonyl, heterocyclyl, benzyl, phenethyl, aryl or    heteroaryl each optionally independently substituted with 1 to 3    substituents chosen from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆ alkoxy,    C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆    alkylamino, C₃₋₆ cycloalkylamino, C₁₋₆ dialkylamino, C₁₋₆    alkylaminocarbonyl, C₁₋₆ acylamino, C₁₋₆ dialkylaminocarbonyl,    hydroxyl, halogen, cyano, nitro, oxo, heterocyclyl, aryl and    heteroaryl, each substituent on R² where possible is optionally    halogenated or substituted with 1 to 3 C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆    alkyl sulfonyl, cyano, aryl, oxo or hydroxyl;-   or R¹ and R² together with the nitrogen atom to which they are    attached form a monocyclic, bicyclic or spirocyclic heterocycle or    monocyclic or bicyclic heteroaryl ring each optionally substituted    with 1 to 3 C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl, C₁₋₆ alkyl sulfonyl,    cyano, aryl, oxo, hydroxyl or halogen each ring substituent being    further optionally halogenated where possible;-   R³ and R^(3′) are independently hydrogen or C₁₋₆ alkyl optionally    halogenated with the proviso that R³ and R^(3′) cannot    simultaneously be hydrogen; or R³ and R^(3′) together with the    carbon atom to which they are attached form a 3- to 6-membered    cycloalkyl or heterocyclic ring each optionally halogenated;-   R⁴ is hydrogen or methyl;-   R⁵ is chosen from

-   m is 0, 1, 2 or 3-   R⁶ is hydrogen, C₁₋₄ alkyl or C₁₋₄alkoxy-   R⁷ and R⁸ are each independently hydrogen, or C₁₋₄ alkyl with the    proviso that both R⁷ and R⁸ cannot be hydrogen; and wherein R⁷ and    R⁸ optionally can cyclize to form a C₃₋₇ cycloalkyl ring;-   R⁹ is C₁₋₆ alkyl or aryl;-   ring B is a 5-6 membered heterocyclic ring;-   n is 0, 1 or 2;-   wherein any carbon atom on the formula (I) or any R substituent    listed above is optionally partially or fully halogenated where    possible;-   or a pharmaceutically acceptable salt thereof.

In another embodiment 2, the invention provides compounds of the formula(I) according to the embodiment immediately above, and wherein

-   ring A is

-   R² is C₁₋₆ alkyl, C₃₋₇ cycloalkyl,    1,1-dioxo-1λ⁶-thiomorpholinylcarbonyl, phenylsulfonyl,    tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl or piperidinyl,    each optionally independently substituted with 1 to 3 substituents    chosen from C₁₋₅ alkyl, C₃₋₇ cycloalkyl, C₁₋₅ alkoxy, C₁₋₅    alkylthio, C₁₋₅ alkylsulfonyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ alkylamino,    C₃₋₆ cycloalkylamino, C₁₋₅ dialkylamino, C₁₋₅ alkylaminocarbonyl,    C₁₋₅ acylamino, C₁₋₅ dialkylaminocarbonyl, hydroxyl, halogen, cyano,    nitro, oxo, phenyl and heterocyclyl chosen from tetrahydropyranyl,    dioxanyl, tetrahydrofuranyl, thiomorpholinyl,    1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyrrolidinyl,    piperidinyl and piperazinyl,-   each R² substituent where possible is optionally halogenated or    substituted with 1 to 3 C₁₋₅ alkyl, C₁₋₅ acyl, methyl sulfonyl,    cyano, phenyl, oxo or hydroxyl;-   or R¹ and R² together with the nitrogen atom to which they are    attached form a ring chosen from thiomorpholinyl,    1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyrrolidinyl,    piperidinyl, piperazinyl, azetidinyl, benzimidazolyl, pyrazolyl,    imidazolyl, triazinyl, indazolyl, indolyl, indolinyl, isoindolyl,    isoindolinyl, and 2-aza-spiro[4.5]dec-2-yl,    1-aza-spiro[4.5]dec-1-yl, 1-aza-spiro[4.4]non-1-yl,    2-aza-spiro[4.4]non-2-yl, 2-aza-spiro[5.5]undec-2-yl,    1-aza-spiro[5.5]undec-1-yl-   each optionally substituted with 1 to 3 C₁₋₆ alkyl, C₁₋₆ alkoxy,    C₁₋₆ acyl, C₁₋₆ alkyl sulfonyl, cyano, phenyl, oxo, hydroxyl and    halogen each ring substituent being further optionally halogenated    where possible;-   R³ and R^(3′) are each methyl or ethyl, each optionally halogenated,    or R³ and R⁴ together with the carbon atom to which they are    attached form a cyclopropyl or cyclobutyl ring each optionally    halogenated.

In another embodiment 3, the invention provides compounds of the formula(I) according to the embodiment described immediately above, and wherein

-   ring A is

-   R¹ is hydrogen or C₁₋₃ alkyl optionally halogenated;-   R² is C₁₋₆ alkyl or C₃₋₇ cycloalkyl optionally independently    substituted with 1 to 3 halogen, one C₃₋₇ cycloalkyl, C₁₋₆ alkoxy or    one heterocyclyl chosen from tetrahydropyranyl, dioxanyl,    tetrahydrofuranyl, thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholinyl,    morpholinyl, pyrrolidinyl, piperidinyl and piperazinyl each    optionally halogenated or substituted with C₁₋₄ alkyl or methyl    sulfonyl;-   or R¹ and R² together with the nitrogen atom to which they are    attached form a ring chosen form thiomorpholinyl,    1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyrrolidinyl,    piperidinyl, azetidinyl, indolyl, indolinyl, isoindolyl,    isoindolinyl, and 2-aza-spiro[4.5]dec-2-yl each optionally    substituted with 1 to 3 C₁₋₄ alkyl, C₁₋₄ alkoxy and halogen each    ring substituent being further optionally halogenated where    possible;-   R³ and R^(3′) are each methyl or ethyl or R³ and R⁴ together with    the carbon atom to which they are attached form a cyclopropyl or    cyclobutyl ring;-   R⁶ is hydrogen or C₁₋₂ alkyl;-   R⁷ and R⁸ are each C₁₋₂ alkyl.

In another embodiment 4, the invention provides compounds of the formula(I) according to the embodiment immediately above, and wherein

-   ring A is

-   R² is methyl optionally substituted with one heterocyclyl chosen    from tetrahydropyranyl, dioxanyl, tetrahydrofuranyl,    thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl,    pyrrolidinyl, piperidinyl and piperazinyl each optionally    halogenated or substituted with C₁₋₄ alkyl or methyl sulfonyl;-   or R¹ and R² together with the nitrogen atom to which they are    attached form a ring chosen form thiomorpholinyl,    1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyrrolidinyl,    piperidinyl, azetidinyl, indolyl and 2-aza-spiro[4.5]dec-2-yl each    optionally substituted with 1 to 3 C₁₋₃ alkyl, C₁₋₃ alkoxy and    halogen each ring substituent being further optionally halogenated    where possible.

In another embodiment 5, the invention provides compounds of the formula(I) according to the embodiment 1, and wherein

-   ring A is

-   R¹ is hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl optionally substituted    with 1-3 C₁₋₆ alkyl, each R¹ or it's substituent is optionally    halogenated;-   R² is cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl,    thiomorpholinylcarbonyl, 1,1-dioxo-1λ⁶-thiomorpholinylcarbonyl,    morpholinylcarbonyl, phenylsulfonyl, phenylcarbonyl, phenyl,    pyridinyl, piperidinyl, pyrimidinyl or thiazolyl, each optionally    independently substituted with 1 to 3 substituents chosen from C₁₋₅    alkyl, C₃₋₅ cycloalkyl, C₁₋₅ alkoxy, C₁₋₅ alkylthio, C₁₋₅    alkylsulfonyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ alkylamino, C₃₋₆    cycloalkylamino, C₁₋₅ dialkylamino, C₁₋₅ alkylaminocarbonyl, C₁₋₅    acylamino, C₁₋₅ dialkylaminocarbonyl, hydroxyl, halogen, cyano and    nitro, each R² substituent where possible is optionally halogenated    or substituted with 1 to 3 C₁₋₅ alkyl or C₁₋₅ alkyl sulfonyl,-   or R¹ and R² together with the nitrogen atom to which they are    attached form a ring chosen from tetrahydropyranyl, dioxanyl,    tetrahydrofuranyl, thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholinyl,    morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl,    benzimidazolyl, pyrazolyl, imidazolyl, triazinyl, indazolyl,    indolyl, indolinyl, isoindolyl, isoindolinyl, and    2-aza-spiro[4.5]dec-2-yl, 1-aza-spiro[4.5]dec-1-yl,    1-aza-spiro[4.4]non-1-yl, 2-aza-spiro[4.4]non-2-yl,    2-aza-spiro[5.5]undec-2-yl, 1-aza-spiro[5.5]undec-1-yl each    optionally substituted with 1 to 3 C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆    acyl, C₁₋₆ alkyl sulfonyl, cyano, phenyl, oxo, hydroxyl or halogen    each ring substituent being further optionally halogenated where    possible;-   R³ and R^(3′) are each methyl optionally halogenated, or R³ and    R^(3′) together with the carbon atom to which they are attached form    a cyclopropyl or cyclobutyl ring each optionally halogenated;-   R⁴ is hydrogen;-   R⁵ is chosen from

-   R⁶ is hydrogen or C₁₋₃ alkyl;-   wherein R⁷ and R⁸ are each C₁₋₃ alkyl or C₃₋₆ cycloalkyl.

In another embodiment 6, the invention provides compounds of the formula(I) according to the embodiment 3, and wherein

-   ring A is

-   R³ and R^(3′) are methyl;-   R⁶ is hydrogen or C₁₋₂ alkyl;    wherein R⁷ and R⁸ are each C₁₋₂ alkyl.

In another embodiment 7, the invention provides compounds of the formula(I) according to the embodiment 6, and wherein

-   ring A is

-   R¹ and R² together with the nitrogen atom to which they are attached    form a ring chosen from thiomorpholinyl,    1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyrrolidinyl,    piperidinyl, azetidinyl, indolyl and 2-aza-spiro[4.5]dec-2-yl each    optionally substituted with 1 to 3 C₁₋₃ alkyl, C₁₋₃ alkoxy, hydroxy    and halogen each ring substituent being further optionally    halogenated where possible.

In another embodiment 8, the invention provides compounds of the formula(I) according to the embodiment described immediately above, and wherein

-   ring A is

In another embodiment 9, the invention provides compounds of the formula(I) according to the embodiment described immediately above, and wherein

-   R¹ and R² together with the nitrogen atom to which they are attached    form a ring chosen from morpholinyl, pyrrolidinyl and piperidinyl,    each optionally substituted with 1 to 3 C₁₋₃ alkyl.

In another embodiment 10, the invention provides compounds of theformula (I) according to embodiment 2, and wherein

-   R² is cyclopropyl, cyclohexyl, tetrahydropyranyl, pyrrolidinyl or    piperidinyl, each optionally independently substituted with 1 to 2    substituents chosen from C₁₋₃ alkyl and C₁₋₂ alkylsulfonyl.

In another embodiment 11, the invention provides compounds of theformula (I) according to embodiment 2, and wherein

-   R² is CF₃—CH₂—CH₂—CH₂—, CH₃—CH₂—CH₂(CH₃)—, cyclopropyl-CH₂—,    hydroxylcyclohexyl, tetrahydrofuranyl-CH₂—;-   ring A is

-   R⁵ is

whereinwherein R⁷ and R⁸ optionally can cyclize to form a C₃₋₇ cycloalkyl ring.

In another embodiment 12, the invention provides compounds of theformula (I) according to embodiment 2, and wherein

-   R² hydroxylcyclohexyl, tetrahydropyranyl, hydroxylpyrrolidinyl or    methylsulfonylpyrrolidinyl;-   ring A is

-   R⁵ is

whereinwherein R⁷ and R⁸ optionally can cyclize to form a C₃₋₇ cycloalkyl ring;

-   R¹ and R² optionally can cyclize to form piperidinyl,    methylsulfonylpiperidinyl.

In another aspect of the invention there is provided a second set ofgeneric embodiments, wherein for each of the above embodiments 1-10 ofthe formula (I), R⁷ and R⁶ can cyclize to form a 4-6 memberedheterocyclic ring.

In another embodiment there is provided a compound of the formula (II)

wherein

of the formula (I) is chosen from column A1-A42 in Table I, and

of the formula (I) is chosen from column B1-B22 in Table I, with theproviso that when column B is B3, B13 or B22, then A must be A20, A23,A38, or A42

TABLE I

A1

B1

A2

B2

A3

B3

A4

B4

A5

B5

A6

B6

A7

B7

A8

B8

A9

B9

A10

B10

A11

B11

A12

B12

A13

B13

A14

B14

A15

B15

A16

B16

A17

B17

A18

B18

A19

B19

A20

B20

A21

B21

A22

B22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A36

A37

A38

A39

A40

A41

A42

In another embodiment, the invention provides made compounds in Table IIwhich can be made in view of the general schemes, examples and methodsknown in the art.

TABLE II

or a pharmaceutically acceptable salt thereof.

Of the above compounds, the following are preferred CB2 agonists:

TABLE III CB2 CB1 EC₅₀ EC₅₀ Compound (nM) (nM)

313 >20000

56 >50000

28 22037

244 >50000

302 >50000

132 >20000

337 >20000

246 >50000

28 44747

21 21534

66 >50000

93 >50000

13 >50000

11 >50000

15 20819

44 >50000

109 >50000

54 >50000

201 >50000

374 >50000

31 >50000

27 >50000

113 >50000

494 >50000

220 >50000

12 36007

300 >50000

42 >50000

7.1 >50000

126 >50000

29 >50000

25 >50000

446 nt

15 37646

195 >50000

69 >50000

1.7 >20000

28 >50000

68 >50000

40 >50000

27 32068

33 >50000

In all the compounds disclosed hereinabove in this application, in theevent the nomenclature is in conflict with the structure, it shall beunderstood that the compound is defined by the structure.

The invention also relates to pharmaceutical preparations, containing asactive substance one or more compounds of formula (I), or thepharmaceutically acceptable derivatives thereof, optionally combinedwith conventional excipients and/or carriers.

Compounds of the invention also include their isotopically-labelledforms. An isotopically-labelled form of an active agent of a combinationof the present invention is identical to said active agent but for thefact that one or more atoms of said active agent have been replaced byan atom or atoms having an atomic mass or mass number different from theatomic mass or mass number of said atom which is usually found innature. Examples of isotopes which are readily available commerciallyand which can be incorporated into an active agent of a combination ofthe present invention in accordance with well established procedures,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, and ³⁶Cl, respectively. An active agent of a combination ofthe present invention, a prodrug thereof, or a pharmaceuticallyacceptable salt of either which contains one or more of theabove-mentioned isotopes and/or other isotopes of other atoms iscontemplated to be within the scope of the present invention.

The invention includes the use of any compounds of described abovecontaining one or more asymmetric carbon atoms may occur as racematesand racemic mixtures, single enantiomers, diastereomeric mixtures andindividual diastereomers. Isomers shall be defined as being enantiomersand diastereomers. All such isomeric forms of these compounds areexpressly included in the present invention. Each stereogenic carbon maybe in the R or S configuration, or a combination of configurations.

Some of the compounds of formula (I) can exist in more than onetautomeric form. The invention includes methods using all suchtautomers.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C₁₋₄alkoxy” is a C₁₋₄alkyl with a terminal oxygen, such asmethoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl and alkynyl groupsshall be understood as being branched or unbranched where structurallypossible and unless otherwise specified. Other more specific definitionsare as follows:

Carbocycles include hydrocarbon rings containing from three to twelvecarbon atoms. These carbocycles may be either aromatic either aromaticor non-aromatic ring systems. The non-aromatic ring systems may be mono-or polyunsaturated. Preferred carbocycles include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certainterms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be usedinterchangeably.

The term “heterocycle” refers to a stable nonaromatic 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 memberedbicyclic heterocycle radical which may be either saturated orunsaturated. Each heterocycle consists of carbon atoms and one or more,preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygen andsulfur. The heterocycle may be attached by any atom of the cycle, whichresults in the creation of a stable structure.

The term “heteroaryl” shall be understood to mean an aromatic 5-8membered monocyclic or 8-11 membered bicyclic ring containing 1-4heteroatoms such as N, O and S.

Unless otherwise stated, heterocycles and heteroaryl include but are notlimited to, for example benzoxazolyl, benzothiazolyl, benzimidazolyl,tetrahydropyranyl, dioxanyl, tetrahydrofuranyl, oxazolyl, isoxazolyl,thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiadiazolyl,triazolyl, thiomorpholinyl, 1,1-Dioxo-1λ⁶-thiomorpholinyl, morpholinyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolidinyl,piperidinyl, piperazinyl, purinyl, quinolinyl, Dihydro-2H-quinolinyl,isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl,indolyl, isoindolyl, benzofuranyl, benzopyranyl and benzodioxolyl.

The term “heteroatom” as used herein shall be understood to mean atomsother than carbon such as O, N, S and P.

In all alkyl groups or carbon chains one or more carbon atoms can beoptionally replaced by heteroatoms: O, S or N, it shall be understoodthat if N is not substituted then it is NH, it shall also be understoodthat the heteroatoms may replace either terminal carbon atoms orinternal carbon atoms within a branched or unbranched carbon chain. Suchgroups can be substituted as herein above described by groups such asoxo to result in definitions such as but not limited to: alkoxycarbonyl,acyl, amido and thioxo.

The term “aryl” as used herein shall be understood to mean aromaticcarbocycle or heteroaryl as defined herein. Each aryl or heteroarylunless otherwise specified includes it's partially or fully hydrogenatedderivative. For example, quinolinyl may include decahydroquinolinyl andtetrahydroquinolinyl, naphthyl may include its hydrogenated derivativessuch as tetrahydronaphthyl. Other partially or fully hydrogenatedderivatives of the aryl and heteroaryl compounds described herein willbe apparent to one of ordinary skill in the art.

As used herein, “nitrogen” and “sulfur” include any oxidized form ofnitrogen and sulfur and the quaternized form of any basic nitrogen. Forexample, for an —S—C₁₋₆ alkyl radical, unless otherwise specified, thisshall be understood to include —S(O)—C₁₋₆ alkyl and —S(O)₂—C₁₋₆ alkyl.

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine, preferablyfluorine. The definitions “partially or fully halogenated”; partially orfully fluorinated; “substituted by one or more halogen atoms”, includesfor example, mono, di or tri halo derivatives on one or more carbonatoms. For alkyl, a nonlimiting example would be —CH₂CHF₂, —CF₃ etc.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, a compound which would have a ‘dangling valency’, or a‘carbanion’ are not compounds contemplated by the inventive methodsdisclosed herein.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester, or any othercompound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound useful for the invention,or a pharmacologically active metabolite or pharmacologically activeresidue thereof. A pharmacologically active metabolite shall beunderstood to mean any compound of the invention capable of beingmetabolized enzymatically or chemically. This includes, for example,hydroxylated or oxidized derivative compounds of the formula (I).

Pharmaceutically acceptable salts include those derived frompharmaceutically acceptable inorganic and organic acids and bases.Examples of suitable acids include hydrochloric, hydrobromic, sulfuric,nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic,salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric,methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric andbenzenesulfonic acids. Other acids, such as oxalic acid, while notthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsand their pharmaceutically acceptable acid addition salts. Salts derivedfrom appropriate bases include alkali metal (e.g., sodium), alkalineearth metal (e.g., magnesium), ammonium and N—(C₁-C₄ alkyl)₄ ⁺ salts.

In addition, within the scope of the invention is use of prodrugs ofcompounds of the formula (I). Prodrugs include those compounds that,upon simple chemical transformation, are modified to produce compoundsof the invention. Simple chemical transformations include hydrolysis,oxidation and reduction. Specifically, when a prodrug is administered toa patient, the prodrug may be transformed into a compound disclosedhereinabove, thereby imparting the desired pharmacological effect.

The compounds of formula I may be made using the general syntheticmethods described below, which also constitute part of the invention.

General Synthetic Methods

The invention also provides processes for making compounds of Formula(I) or Formula (II). In all Schemes, unless specified otherwise, R¹, R²,R³, R^(3′), R⁴, R⁵ and A in the Formulas below shall have the meaning ofR¹, R², R³, R^(3′), R⁴, R⁵ and A in Formula (I) or Formula (II) of theinvention described herein above.

Optimum reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures, and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Typically, reaction progressmay be monitored by thin layer chromatography (TLC), if desired, andintermediates and products may be purified by chromatography on silicagel and/or by recrystallization.

The examples which follow are illustrative and, as recognized by oneskilled in the art, particular reagents or conditions could be modifiedas needed for individual compounds without undue experimentation.Starting materials and intermediates used, in the Schemes below, areeither commercially available or easily prepared from commerciallyavailable materials by those skilled in the art.

The compounds of Formula (I) or Formula (II) may be synthesizedaccording to Scheme 1:

As illustrated in scheme 1, reaction of an acid of formula (III) withreagents such as thionyl chloride or oxalyl chloride provides thecorresponding acid chloride of formula (IV). Reaction of this acidchloride (IV) with an amine of formula (V), in a suitable solvent, inthe presence of a suitable base such as N,N-diisopropylethylamine,provides an amide of formula (VI).

Alternatively, the acid of formula (III) above may also be coupled withthe corresponding amine of formula (V), under standard couplingconditions, to provide an amide of formula (VI). Standard peptidecoupling reactions known in the art (see for example M. Bodanszky, 1984,The Practice of Peptide Synthesis, Springer-Verlag) may be employed inthese syntheses. An example of suitable coupling conditions is treatmentof a solution of the carboxylic acid in a suitable solvent such as DMFwith EDC, HOBT, and a base such as diisopropylethylamine, followed bythe desired amine.

Reaction of the intermediate of formula (VI) with an amine of formula(VII), in a suitable solvent, in the presence of a suitable base such ascesium carbonate, provides a compound of Formula (I) or Formula (II).

The compounds of Formula (I) or Formula (II) may be prepared accordingto Scheme 2:

As outlined in scheme 2, reaction of an amide of formula (VI) with anamine of formula (VIII), in a suitable solvent, in the presence of asuitable base such as cesium carbonate, provides an amine of formula(IX). Reaction of the intermediate amine of formula (IX) with an acidchloride of formula (Xa) or a sulfonyl chloride of formula (Xb), in asuitable solvent, in the presence of a suitable base, provides acompound of Formula (I) or Formula (II) wherein R²═R—C(O)— or R—SO₂—

The compounds of Formula (I) or Formula (II) may be synthesized asoutlined in Scheme 3:

As illustrated in scheme 3, reaction of an amine of formula (IX) with acompound of formula (XI), in a suitable solvent, in the presence of asuitable base such as cesium carbonate, provides a compound of Formula(I) or Formula (II)

Alternatively, reaction of an amine of formula (IX) with a compound offormula (XII) wherein Hal=bromo or iodo, in a suitable solvent, in thepresence of a suitable base such as sodium hydride, provides a compoundof Formula (I) or Formula (II).

The compounds of Formula (I) or Formula (II) may be synthesized as shownin Scheme 4:

As shown in scheme 4, reaction of an amino acid of formula (XIII) withan aldehyde of formula (XIV), under standard reductive aminationconditions, provides an amine of formula (XV). Further reaction of amineof formula (XV) with an aldehyde of formula (XVI) provides thecorresponding amine of formula (XVII). Coupling the intermediate offormula (XVII) with an amine of formula (V), as in scheme 1, provides acompound of Formula (I) or Formula (II) wherein R¹═R^(a)—CH₂— andR²═R^(b)—CH₂—

The compounds of Formula (I) or Formula (II) may be synthesizedaccording to Scheme 5:

As illustrated above in scheme 5, reaction of a bromo ester of formula(XVIII) with an amine of formula (VIII), in a suitable solvent, providesthe corresponding N-substituted product of formula (XIX). Reaction ofthe compound (XIX) with a halide of formula (XII), in a suitablesolvent, in the presence of a suitable base, provides a tertiary amineof formula (XX). Ester hydrolysis under standard conditions provides anacid of formula (XXI). Coupling the acid formula (XXI) with an amine offormula (V), as in scheme 1, provides a compound of Formula (I) orFormula (II).

Further modification of the initial product of Formula (I) or Formula(II), by methods known in the art and illustrated in the Examples below,may be used to prepare additional compounds of this invention.

EXAMPLES Method A Synthesis of Example 1

Step 1: Synthesis of Compound 2

To a flask containing 2-bromo-2-methyl-propionic acid (1) (0.6 g, 3.5mmol) under nitrogen is added thionyl chloride (2 mL). The reactionmixture is heated to 70° C. where it is maintained for 2 h. After thistime, the reaction is cooled to room temperature and concentrated underreduced pressure. The crude acid chloride is used without furtherpurification.

The crude acid chloride is dissolved in dichloromethane (DCM) (5 mL) andN,N-diisopropylethylamine (1 mL, 5.7 mmol) is added followed by3-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-5-ylamine (0.6 g, 3.5 mmol).

The reaction is stirred for 16 h at room temperature. After this time,additional 2-bromo-2-methyl-propionic acid (0.3 g, 1.7 mmol) isactivated as its acid chloride, as described above) and added to thereaction mixture. After further 1.5 h stifling, the mixture is washedwith saturated aqueous NaHCO₃ solution (×2), brine and the organic layeris separated, dried (MgSO₄) and concentrated under reduced pressure. Thecrude product is purified by chromatography (silica, eluent: heptanes,20% ethyl acetate) to provide compound 2 (0.6 g, 51%);

According to the above procedure the following intermediates aresynthesised:

TABLE 1 Intermediate Yield LC Method and No. Structure (%) Retentiontime [min] m/z [M + H] I (compound 2)

51 LC Method b: 1.90 319/321 II

54 LC Method b: 1.96 319/321

Step 2: Synthesis of Example 1

To a solution of 4-aminotetrahydropyran (0.1 g, 0.94 mmol) in THF (2 mL)are added Cs₂CO₃ (0.6 g, 1.84 mmol) and compound 2 (0.3 g, 0.94 mmol).The reaction is heated to 50° C. for 3 h. The solvent is then removedunder reduced pressure and the residue is partitioned between DCM and 1Maqueous HCl solution. The acidic aqueous layer is basified with 5Naqueous NaOH solution and extracted with DCM (3×10 mL). The combinedorganic extracts are washed with brine, dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude product is purified bycolumn chromatography (silica, eluent: heptanes, 50% ethyl acetate) toyield example 1 (0.15 g, 41%). LC-MS (LC Method a): retention time: 2.40min, m/z 340 [M+H]

Compounds listed in Table IV under method A are made following thisprocedure.

Method B Synthesis of Example 2

Example 2 Step 1: Synthesis of Compound 3

To a flask containing compound 1 (3 g, 18 mmol) under nitrogen is addedthionyl chloride (6.6 mL). The reaction mixture is heated to 70° C.where it is maintained for 3 h. After this time, the reaction is cooledto room temperature and concentrated under reduced pressure. The crudeacid chloride is used without further purification.

The crude acid chloride is dissolved in THF (11 mL) andN,N-diisopropylethylamine (3.1 mL, 18 mmol) is added, followed by3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-ylamine(4.3 g, 18 mmol). The reaction is stirred for 16 h at 40° C. The mixtureis washed with saturated aqueous NaHCO₃ solution (×2), brine and theorganic layer is separated, dried (MgSO₄) and concentrated under reducedpressure. Purification of the residue by chromatography (silica, eluent:heptanes, 20% ethyl acetate) allows separation and isolation of compound3 (1 g, 18%), m/z 305/307 [M+H⁺], from compound 4 (0.9 g, 13%), LC-MS(LC Method b): retention time: 2.35 min, m/z 411/413 [M+Na+H].

Step 2: Synthesis of Example 2

To a solution of 4-aminotetrahydropyran (0.05 g, 0.5 mmol) in THF (3 mL)are added Cs₂CO₃ (0.3 g, 1 mmol) and compound 3 (0.15 g, 0.5 mmol). Thereaction is heated to 50° C. for 18 h. The solvent is then removed underreduced pressure and the residue is partitioned between DCM and 1Maqueous HCl solution. The acidic aqueous layer is basified with 5Naqueous NaOH solution and extracted with DCM (3×10 mL). The combinedorganic extracts are washed with brine, dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude product is purified twiceby column chromatography (silica, eluent: heptanes, 20% EtOAc) followedby trituration with 1M HCl in dioxane to yield the hydrochloride salt ofexample 2 (0.04 g, 22%). LC-MS (LC Method a): retention time: 2.16 min,m/z 326 [M_(freebase)+H]

Compounds listed in Table IV under method B are made following thisprocedure.

Method C Synthesis of Example 3

Step 1: Synthesis of Compound 4

To a flask containing compound 1 (20.85 g, 125 mmol) in DCM (150 mL)under nitrogen is added oxalyl chloride (16.2 mL, 187.3 mmol), followedby DMF (5 drops). The reaction mixture is stirred at room temperaturefor 16 h and then concentrated under reduced pressure. The crude acidchloride, used without further purification,

is dissolved in toluene (50 mL) and added dropwise over 10 min to asolution of N,N-diisopropylethylamine (32.6 mL, 187 mmol) and3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-ylamine(15 g, 62.4 mmol) in toluene (300 mL) at 50° C. The reaction is stirredfor 4 h at 60° C. The reaction mixture is concentrated under reducedpressure and the residue is partitioned between DCM (300 mL) and water(250 mL). The organic layer is separated and dried over Na₂SO₄, filteredand concentrated under reduced pressure. The crude orange oil isdissolved in diethyl ether and precipitated by addition of n-heptanes.The precipitate is isolated by filtration and washed sparingly withdiethyl ether/heptanes to yield the first crop (9 g) of compound 4 asoff-white solid. The mother liquor is concentrated and a second crop(3.3 g) is isolated by crystallisation/precipitation from diethylether/heptanes. The mother liquor is concentrated under reduced pressureand the residual orange oil filtered through silica (eluent: heptanes,20% ethyl acetate), the filtrate is concentrated. The residue isdissolved in diethyl ether and the third crop (3.1 g) is isolated bydiethyl ether/heptanes treatment as described above. The combined yieldof crop 1-3 is 15.4 g. Yield 63%; LC-MS (LC Method b): retention time:2.35 min, m/z 411/413 [M+Na+H].

Step 2: Synthesis of Compound 5

A solution of N-methyl-(tetrahydro-pyran-4-yl)-amine (0.25 g, 2.17mmol), Cs₂CO₃ (1.41 g, 4.34 mmol) and compound 4 (0.85 g, 2.17 mmol) inTHF (20 mL) is stirred at room temperature for 72 h. The reactionmixture is filtered through Celite®, the solids are washed with ethylacetate and DCM and the filtrate is concentrated under reduced pressure.The residue is purified by column chromatography (silica, eluent:heptanes, 50-100% ethyl acetate) to yield 374 mg of compound 5. Yield41%; LC-MS (LC Method b): retention time: 1.51 min, m/z 424 [M+H]

The following amines are synthesised by adaptation of the aboveprocedure with the following modification to be noted:

For intermediate II and III: excess of the corresponding amine (2.5 equ)and Cs₂CO₃ (2 equ.) are used, the work-up procedure includes a wash ofthe organic layer with 10% aqueous citric acid solution followed bybrine and the product is isolated by column chromatography (silica,eluent heptanes, 30% ethyl acetate).

For intermediate XI the reaction is stirred for 48 h at ambienttemperature.

For intermediate XII and X: the reaction mixture is filtered throughcelite and washed with DCM. The solvent is removed under reducedpressure and the product purified by column chromatography (silica,eluent; heptanes, 0-50% ethyl acetatec)

According to the above procedure the following intermediates aresynthesised:

TABLE 2 LC Method and Intermediate Yield Retention No. Structure [%]time [min]] m/z [M + H] III (compound 5)

41 LC Method b: 1.51 424 IV

68 LC Method b: 1.46 394 V

51 LC Method b: 2.11 423 VI

27 not available/ see Footnote a 438 VII

51 not available/ see Footnote b 382 VIII

66 not available/ see Footnote c 487 IX

27 LC Method a: 2.89 424 X

27 LC Method b: 2.05 424 XI

34 LC Method a: 2.74 410 XII

31 LC Method b: 1.48 501 XIII

n.d.# LC Method b: 1.50 436 XIV

28 LC Method b: 1.54 408 XV

97 LC Method b: 1.51 438 XVI

n.d.# LC Method b: 1.34 396 XVII

n.d.# LC Method b: 1.69 424 XVIII

n.d.# LC Method b: 1.45 499 [M − H] XIX

n.d.# LC Method b: 1.71 436 [M − H] XX

n.d.# LC Method b: 1.43 487 XXI

55 LC Method b: 1.48 424 XXII

56 LC Method b: 1.33 394 XXIII

78 LC Method b: 1.70 380 XXIV

32 LC Method b: 1.99 438 [M − H] XXV

22 LC Method b: 1.29 380 XXVI

n.d.# LC Method b: 1.49 410 XXVII

34 LC Method b: 1.64 420 [M − H] a) n.d.# intermediate is carriedthrough to the next step without further purificationa) Intermediate VI:¹H NMR (400 MHz, chloroform-d) δ ppm 1.26 (6H, s), 1.34 (3H, s), 1.37(3H, s), 1.47-1.83 (11H, m), 2.18 (2H, d, 7.2 Hz), 2.22 (3H, s),3.36-3.50 (3H, m), 3.77-3.82 (3H, m), 3.99 (2H, m), 4.57 (1H, m), 6.32 &6.38 (1H, 2s), 9.4-9.8 (1H, br) b) Intermediate VII: ¹H NMR (400 MHz,chloroform-d) δ ppm 1.07 (6H, d, J = 6.4 Hz), 1.32-1.37 (12H, m),1.46-1.84 (6H, m), 2.19 (3H, s), 2.98 (1H, q), 3.37 (1H, d, J = 9.6 Hz),3.45-3.50 (1H, m), 3.76-3.81 (2H, m), 4.57 (1H, t, J = 6.8 Hz), 6.32(1H, s), 10.10 (1H, br) c) Intermediate VIII: ¹H NMR (400 MHz,chloroform-d) δ ppm 1.25 (12H, s), 1.31-1.76 (10H, m), 2.70 (2H, t, 11.2Hz), 2.80 (3H, s), 3.31-3.42 (6H, m), 3.62-3.66 (2H, m), 4.53 (1H, s),6.25 (1H, s), 6.80 (1H, br)

Step 3: Synthesis of Example 3

To a solution of compound 5 (806 mg, 1.9 mmol) in DCM/ethanol (1/1, 16mL) is added polymer-supported tosic acid (MP-TsOH (65), loading 3.3mmol/g, 1.74 g). The mixture is shaken on an orbital-shaker at roomtemperature for 18 h. The resin is isolated by filtration and washedwith DCM and methanol. The product is then released form the resin with7M solution of ammonia in methanol. The resin is further rinsed withmethanol and DCM. Concentration of the basic filtrate gives a clear oilwhich is triturated with diethyl ether/heptanes to afford 549 mg ofexample 3 as a white solid. Yield 85%, LC-MS (LC Method a): retentiontime: 2.17 min m/z 410 [M+H]; mp 129-131° C.

Compounds listed in Table IV under method C are made following thisprocedure, with the following modification for examples 7-9, and 20:Pyridinium p-toluenesulfonate (1.2 equ) is used instead of MP-TsOH andthe reaction is performed under refluxing conditions (4 h) in EtOHinstead of DCM/ethanol.

Example 86-87 are separated by chiral preparative LC.

Example 4 and 5 are converted into the oxalate salt by stirring in thepresence of oxalic acid (1 equ) in ethanol at 50° C., followed byconcentration under reduced pressure.

Examples 42, 43, 45, 47, 48, 49, 51, 53, 56, 57, 60, 63, 64, 68, 86, 87are converted into the hydrochloride salt by stirring in the presence of1M HCl solution in diethyl ether (2 eq) at room temperature, followed byconcentration under reduced pressure.

Method D Synthesis of Example 6

A solution of 2-methylpiperidine (40 mg, 0.33 mmol), Cs₂CO₃ (218 mg,0.66 mmol) and compound 4 (130 mg, 0.33 mmol) in THF (10 mL) is heatedto 55° C. for 3 h in a pressure tube. After cooling to room temperature,the reaction mixture is diluted with ethyl acetate (40 mL) and washedwith brine (2×15 mL), dried (MgSO₄), filtered and concentrated underreduced pressure. The residue is purified by column chromatography(silica, eluent: heptanes, 10% ethyl acetate) and then using a FlashSCX-2 cartridge (Isolute®) (eluent: DCM, methanol then 5% NH₃/MeOH)which removes the tetrahydropyranyl protecting group. Final purificationusing silica, eluent: heptanes, 10% ethyl acetate) yield 23 mg ofexample 6. Yield 22%. LC-MS (LC Method a): retention time: 2.35 min, m/z324 [M+H]

A portion of example 6 is converted into its hydrochloride salt bystirring in the presence of 1M HCl solution in diethyl ether (2 equ.) atroom temperature, followed by concentration under reduced pressure.

Compounds listed in Table IV under method D are made following thisprocedure

Method E Synthesis of Example 10

Example 12 (80 mg, 0.24 mmol, prepared according to Method A) and 600 mg(2.35 mmol) of aluminum tribromide are dissolved in ethanethiol (4 mL,CAUTION: stench) and stirred at room temperature for 3 h. The reactionis quenched by addition of water (8 mL) and acidified by carefuladdition of 1 M aqueous HCl solution to pH 4-5. The reaction mixture isextracted with ethyl acetate (3×10 mL) and the combined organic layersare washed with brine, dried over Na₂SO₄ and filtered. The filtrate isconcentrated under reduced pressure and the residue purified by columnchromatography (silica, eluent: DCM, 50% ethyl acetate) to afford 50 mgof example 10. Yield 65%, LC-MS (LC Method a): retention time: 2.14 min,m/z 326 [M+H]

Compounds listed in Table IV under method E are made following thisprocedure

Method F Synthesis of Example 46

To a solution of example 42 (0.34 g, 1.01 mmol) and NaH (0.12 g, 3.04mmol, 60% dispersion in mineral oil,) in THF (6 mL) is added methyliodide (95 μL, 1.52 mmol). The reaction mixture is stirred at roomtemperature for 18 h and filtered through celite. The crude product ispurified by preparative HPLC (neutral method) to yield 53 mg of example46 as a colourless oil. Yield: 17%, LC-MS (LC Method a): retention time:2.60 min, m/z 368 [M+H]. example 46 is converted to the hydrochloridesalt by stirring in the presence of 2M solution of hydrogen chloride indiethyl ether (1 mL) at room temperature, followed by concentrationunder reduced pressure.

Compounds listed in Table IV under method F are made following thisprocedure

Method G Synthesis of Example 50

Step 1: Synthesis of Compound 6

A solution of methylamine (2.89 mL, 23.1 mmol), Cs₂CO₃ (0.75 g, 2.3mmol) and compound 4 (0.45 g, 1.2 mmol) in THF (10 mL) is heated to 65°C. in a sealed tube for 3 h. The reaction mixture is cooled and dilutedwith ethyl acetate (20 mL). The mixture is washed with brine (8 mL). Theorganic layer is dried (MgSO₄), filtered and the filtrate isconcentrated under reduced pressure. The crude product is purified bycolumn chromatography (silica, eluent: heptanes, 0-50% ethyl acetate) toyield 0.29 g of compound 6. Yield: 74%; LC-MS (LC Method b): retentiontime: 1.24 min, m/z 340 [M+H].

Step 2: Synthesis of Compound 7

To a solution of compound 6 (0.2 g, 0.59 mmol) andN,N-diisopropylethylamine (0.2 mL, 1.18 mmol) in THF (8 mL) is added(tetrahydro-pyran-4-yl)-acetyl chloride (0.11 g, 0.59 mmol). Thereaction is heated to 60° C. for 18 h and the solvent is removed underreduced pressure. The residue is dissolved in ethyl acetate (20 mL) andwashed with water (2×5 mL) and brine (2×5 mL). The organic layer isdried (MgSO₄), filtered and the filtrate is concentrated under reducedpressure. The residue is purified by column chromatography (silica,eluent: heptanes, 0-50% ethyl acetate) to yield 0.25 g of compound 7;yield: 94%, LC-MS (LC Method b): retention time: 1.90 min, m/z 464[M−H].

According to the above method the following intermediates aresynthesised with the following modifications to be noted:

For intermediate XXX and XXXIII, the corresponding acid is convertedinto its acidchloride by treatment with oxalylchloride (4 equ.) and DMF(cat) in DCM at room temperature for 4 h. The reaction mixture isconcentrated under reduced pressure and the crude acid chloride is usedin the above procedure without further purification.

Intermediates XXXI and XXXII are synthesised using standard amidecoupling conditions: 1 equ of compound 6 is coupled with thecorresponding acid (1 equ) using EDC.HCl (3 equ) and DMAP (1 equ) inacetonitrile. The reaction mixture is stirred at room temperature for 18h and the concentrated under reduced pressure. The residue is purifiedby column chromatography (silica, eluent:n-heptanes, 30% ethyl actetate)to afford the desired intermediate.

According to the above procedure the following intermediates aresynthesised:

TABLE 3 LC Method and Intermediate Yield Retention No. Structure [%]time [min] m/z [M + H] XXVIII (compound 7)

94 LC Method b: 1.90 464 [M − H] XXIX

22 LC Method b: 1.83 474 [M + Na] XXX

86 LC Method b: 1.89 474 [M + Na] XXXI

69 LC Method b: 2.08 486 [M + Na] XXXII

82 LC Method b: 2.11 500 [M + Na] XXXIII

35 LC Method b: 2.10 458 [M + Na]

Step 3: Synthesis of Example 50

Compound 7 is deprotected by shaking in the presence ofpolymer-supported tosic acid (MP-TsOH (65), loading 3.3 mmol/g, 0.6 g)on an orbital shaker for 18 h. The resin is removed by filtration andwashed with DCM. The product is released from the resin by treatmentwith 7M ammonia in methanol and the filtrate is concentrated underreduced pressure and the residue is purified by preparative HPLC(neutral method) to afford 40 mg of example 50. Yield 18%, LC-MS (LCMethod a): retention time: 3.06 min, m/z 382 [M+H].

Compounds listed in Table IV under method G are made following thisprocedure

Method H Synthesis of Example 52

Step 1: Synthesis of Compound 9

To a solution of compound 6 (0.2 g, 0.59 mmol, prepared according toMethod G, step 1) and Cs₂CO₃ (0.38 g, 1.18 mmol) in THF (3 mL) is addedcompound 8 (115 mg, 1.0 mmol, prepared as described in Gosh, A. K. etal. J. Med. Chem. 1993, 36, 2300-2310). The reaction is heated to 65° C.for 3 h in a sealed tube and diluted in ethyl acetate (12 mL). Theorganic layer is washed with brine (8 mL) and dried (MgSO₄). The solventis removed under reduced pressure and purified by column chromatography(silica, eluent: heptanes, 0-50% ethyl acetate) to afford 0.2 g ofcompound 9. Yield: 12%; LC-MS (LC Method b): retention time: 1.37 min,m/z 438 [M+H].

Step 2: Synthesis of Example 52

To a solution of compound 9 in DCM/methanol (1/1, 4 mL) is addedpolymer-supported tosic acid (MP-TsOH (65), loading 3.3 mmol/g, 0.28 g)and the reaction mixture is shaken on an orbital shaker for 18 h. Theresin is removed by filtration and washed with DCM. The product isreleased from the resin by treatment with 7M ammonia solution inmethanol and the resin is further washed with methanol and DCM. Thefiltrate is concentrated under reduced pressure. The residue is purifiedby preparative LC (neutral method) to afford 69 mg of example 52 as aclear oil, yield 36%, LC-MS (LC Method a): retention time: 2.19 min, m/z354 [M+H], which is converted in its hydrochloride salt by treatmentwith 2M HCl in diethyl ether (0.12 mL) and concentration under reducedpressure. The crude material is recrystallised from ethylacetate/heptanes to afford the hydrochloride salt of example 52 as awhite crystalline solid.

Compounds listed in Table IV under method H are made following thisprocedure

Method I Synthesis of Example 54

Step 1: Synthesis of Compound 10

A solution of (S)-sec-butylamine (0.3 g, 4.1 mmol), Cs₂CO₃ (2.67 g, 8.2mmol) and compound 4 (1.59 g, 4.1 mmol) in THF (10 mL) is stirred atroom temperature for 18 h. The reaction mixture is heated to 50° C. for1 h and the reaction is filtered through celite. The solids are washedwith DCM and ethyl acetate and the filtrate is concentrated underreduced pressure to afford a yellow oil. This residue is purified bycolumn chromatography (silica, eluent: heptanes, 50% ethyl acetate) toyield 0.65 g of compound 10. Yield: 42%, LC-MS (LC Method b): retentiontime: 1.38 min, m/z 382 [M+H].

The following intermediates are made according to the above procedure.

According to the above procedure the following intermediates aresynthesised:

TABLE 4 LC Method and Intermediate Retention time m/z No. StructureYield [%] [min] [M + H] XXXIV (compound 10)

25 LC Method b: 1.38 382 XXXV

22 LC Method b: 1.29 380 XXXVI

37 LC Method b: 1.47 501 XXXVII

48 LC Method b: 1.50 471 [M − H] XXXVIII

50 LC Method b: 1.50 471 [M − H] XXXIX

66 LC Method b: 1.43 501

Step 2: Synthesis of Compound 11

To a solution of the compound 10 (392 mg, 1.02 mmol) in THF (3 mL) isadded sodium hydride (41 mg, 1.02 mmol, 60% dispersion in mineral oil)and methyl iodide (64 μl, 1.02 mmol). The reaction mixture is heated to70° C. for 1 h in a microwave. The reaction mixture is concentratedunder reduced pressure and the residue is dissolved in methanol andfiltered. The filtrate is concentrated under reduced pressure and thecrude material is purified by preparative HPLC (neutral method) toafford 137 mg of compound 11 as a clear oil. Yield: 34%, LC-MS (LCMethod b): retention time: 1.25 min, m/z 396 [M+H].

The following intermediates are made according to the above procedure.

TABLE 5 LC Method and Intermediate Yield Retention time No. Structure[%] [min] m/z [M + H] XXXX (compound 11)

33 LC Method b: 1.25 396 XLI

59 LC Method b: 1.22 394 XLII

60 LC Method b: 1.63 515 XLIII

52 LC Method b: 1.63 515 XLIV

36 LC Method b: 1.94 485 [M − H] XLV

49 LC Method b: 1.94 485 [M − H]

Step 3: Synthesis of Example 54

To a solution of compound 11 (137 mg, 0.34 mmol) in DCM/methanol (1/1,10 mL) is added polymer-supported tosic acid (MP-TsOH (65), loading 3.3mmol/g, 0.31 g). The mixture is shaken on an orbital-shaker at roomtemperature for 18 h. The resin is isolated by filtration and washedwith DCM. The product is then released from the resin with 2M solutionof ammonia in methanol. Concentration of the basic filtrate affords 88mg of example 54. Yield: 63%, LC-MS (LC Method a): retention time: 2.35min, m/z 312 [M+H].

Compounds listed in Table IV under method I are made following thisprocedure with the following modifications to be noted:

Example 54, 55, 84, 85 are converted into the hydrochloride salt bystirring in the presence of hydrogen chloride in diethyl ether (2M, 1mL) at room temperature, followed by concentration under reducedpressure.

Method J Synthesis of Example 27

Step 1: Synthesis of Compound 13

A high pressure vessel on the HEL 100 system containing compound 12 (2.5g; 24.244 mmol) and tetrahydro-pyran-4-carbaldehyde (5.05 mL; 48.487mmol) is added palladium hydroxide, 20% on carbon, wet (3.405 g; 10 mol%; 2.424 mmol) and 50 mL of ethanol. The reaction is subjected to 400psi H₂ at 50° C. for 40 h. After this time, the reaction is cooled toroom temperature and filtered through Celite®. The Celite® is rinsedwith methanol and water.

The combined filtrates are concentrated and slurried in dichloromethane,then filtered to afford compound 13 as a white solid (3.95 g; 81%),LC-MS (LC Method h): retention time 0.32 min, m/z 202 [M+H]⁺

Step 2: Synthesis of Compound 14

A high pressure vessel on the HEL 100 system containing compound 13 (1g; 4.969 mmol) and formaldehyde, 37% in water (0.74 mL; 9.937 mmol) isadded palladium hydroxide, 20% on carbon, wet (0.698 g; 10 mol %; 0.497mmol) and 30 mL of ethanol. The reaction is subjected to 400 psi H₂ at100° C. for 27.5 h. After this time, the reaction is cooled to roomtemperature and filtered through Celite®. The Celite® is rinsed withmethanol and water. The combined filtrates are concentrated to affordcompound 14 as a colorless oil (1.364 g; quantitative), LC-MS (LC Methodh): retention time 0.32 min, m/z 216 [M+H]⁺

Step 3: Synthesis of Example 27

To a vial containing compound 14 (0.2 g; 0.929 mmol) is addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.530 g; 1.394 mmol) and N,N-diisopropylethylamine(0.579 mL; 3.252 mmol). The solution is stirred at room temperature for30 minutes. To a vial containing3-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-isoxazol-5-ylamine (0.199 g;0.929 mmol) is added N,N-dimethylformamide (2 mL) and sodium hydride(0.093 g; 2.323 mmol) at 0° C. To this solution is added the activatedester. Once addition is complete, the cold bath is removed and thereaction warmed to room temperature and stirred for 1 h. The reaction isquenched with methanol/water and concentrated under reduced pressure.Purification is done by reverse phase HPLC to afford example 27 (0.107g; 28%), LC-MS (LC Method c): retention time 0.97 min, m/z 412 [M+H]⁺.

Compounds listed in Table IV under method J are made following thisprocedure with the following modifications to be noted: for example 26,28, and 32 TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate) is used as the coupling reagent instead of HATU asdescribed in step 3.

Compounds listed in Table IV under method J are made following thisprocedure

The following intermediates are made according to the above procedure.

TABLE 6 Intermediate LC Method and No. Structure Yield [%] Retentiontime [min] m/z [M + H] XLVI

crude LC Method d: 1.08 422 XLVII

crude LC Method d: 1.08 424 XLVIII

31 LC Method c:1.08 450 XLIX

23 LC Method c:, 1.70 609 L

23 LC Method c:, 1.80 595

Method J1

Same as Method C step 3.

Compounds listed in Table IV under Method J1 are made following thisprocedure.

Method J2 Synthesis of Example 30

Intermediate XLIX (0.127 g; 0.209 mmol) is diluted with 3 mL methanoland HF pyridine complex (0.130 ml; 1.045 mmol; 70%) is added. Thereaction is heated at 45° C. in a sealed tube for 7 days adding aliquotsof HF pyridine complex on a daily basis. Concentrated and purified bypreparative HPLC. Pooled product fractions and concentrated. Diluted inmethanol and passed through a cartridge containing MP-Carbonate resin toneutralize molecule from trifluoroacetic acid contained in HPLC mobilephase to afford example 30 (0.024 g; 31.1%); LC-MS (LC method c):retention time 0.40 min, m/z 371 [M+H⁺]

Compounds listed in Table IV under Method J2 are made following thisprocedure.

Method K Synthesis of Example 38

Step 1: Synthesis of Compound 16

Compound 15 (6.4 mL, 49.4 mmol) is dissolved in 100 mL of acetonitrileunder nitrogen and potassium iodide (739 mg, 4.5 mmol) is added followedby the addition of potassium carbonate (13.7 g, 98.9 mmol) and4-aminotetrahydropyran (5 g, 49.4 mmol). The reaction mixture is heatedin 90° C. oil bath for 16 hours, After this time, the reaction mixtureis cooled to room temperature and methyl 2-bromoisobutyrate (1.6 mL,12.4 mmol) and potassium iodode (184.5 mg, 1.11 mmol) are added and thereaction mixture is heated in 90° C. oil bath for 18 hours. After thistime, the reaction mixture is cooled to room temperature and filteredthrough a glass funnel and the solid is washed with acetonitrile. Thefiltrate is concentrated under reduced pressure. Purification of theresidue by flash chromatography on silica gel using ethylacetate/heptane provides compound 16 (36%), LC-MS (LC method d):retention time: 0.27 min, m/z 202 [M+H⁺].

The following intermediates are made following the above procedure:

TABLE 7 Intermdediate LC Method and No. Structure Yield [%] Retentiontime [min] m/z [M + H] LI (compound 16)

36 LC Method d: 0.27 202 LII

31 LC Method d: 0.60 293 Notes: starting material for intermediate I isethyl 2-bromoisobutyrate.

Step 2: Synthesis of Compound 17

Methyl iodide (2.5 mL, 39.9 mmol) is added dropwise to a mixture ofcompound 16 (4.38 g, 17.7 mmol) and potassium carbonate (10.94 g, 79.1mmol) in 74 mL of DMF. The reaction mixture is stirred at roomtemperature for 18 hours. After this time, methyl iodide (1 mL, 16 mmol)is added and the reaction mixture is stirred at room temperature for 65hours. After this time, the reaction mixture is filtered and the solidis washed with ethyl acetate. The filtrate is concentrated under reducedpressure. Purification of the residue by flash chromatography on silicagel using ethyl acetate/heptane provides compound 17 (78%), LC-MS(Method d): retention time: 0.27 min, m/z 216 [M+H⁺].

The following intermediates are made following the above procedure:

TABLE 8 Intermediate LC Method and No. Structure Yield [%] Retentiontime [min] m/z [M + H] LIII (compoun 17)

78 LC Method d: 0.27 216 LIV

88 LC Method d: 1.27 307

Step 3: Synthesis of Compound 18

Compound 17 (3.24 g, 13.8 mmol) is dissolved in 14 mL of methanol in apressure tube and sodium hydroxide aqueous solution (4N, 13.8 mL, 55.3mmol) is added and the reaction mixture is heated in 80° C. oil bath for3 hours. After this time, the reaction mixture is concentrated underreduced pressure and the residue is neutralized to pH ˜7 by adding 1NHCl aqueous solution. The resulting solution is diluted withacetonitrile and dried in lyophilizer for 18 hours. After this time, thesolid is suspended in acetone and filtered. The filtrate is concentratedunder reduced pressure to afford compound 18 (100%), LC-MS (LC Methodd): retention time: 0.29 min, m/z 202 [M+H⁺].

The following intermediates are made following the above procedure:

TABLE 9 Intermediate LC Method and No. Structure Yield [%] Retentiontime [min] m/z [M + H] LV compoun 18)

100 LC Method d: 0.29 202 LVI

33 LC Method d: 0.32 279

Step 4: Synthesis of Example 38

To a vial containing compound 18 (142 mg, 0.707 mmol) in 1 mL of DMF isadded O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (272 mg, 0.848 mmol) and diisopropylethylamine (0.27mL, 1.55 mmol). The mixture is stirred at room temperature for 1 hour.To a vial containing compound 25 (149 mg, 0.707 mmol) in 1.2 mL of DMFis added sodium hydride in mineral oil (60%, 62 mg, 1.55 mmol). Themixture is stirred at room temperature for 15 minutes. To this solutionis added dropwise the activated ester. The reaction mixture is stirredat room temperature for 1.5 hours. After this time, the reaction mixtureis concentrated under reduce pressure to remove the solvent. The residueis quenched with saturated sodium bicarbonate aqueous solution andextracted with ethyl acetate twice. The organics are combined and washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Purification of the residue by flash chromatography on silicagel using methanol/methylene chloride provides example 38 (17%), LC-MS(LC method d): retention time 1.03 min, m/z 394 [M+H⁺].

Compounds listed in Table IV under Method K are made following thisprocedure.

Also, the following intermediates are made following this procedure.

TABLE 10 Interme- LC Method and diate No. Structure Yield [%] Retentiontime [min] m/z [M + H] LVII

45 LC Method f: 1.28 485 LVIII

quantitative LC Method c:, 1.12 487

Method K1

Same as Method C step 3.

Compounds listed in Table IV under Method K1 are made following thisprocedure.

Method L Synthesis of Example 36

Step 1: Synthesis of Compound 19

To a pressure vessel containing compound 1 (1.25 g, 7.49 mmol) undernitrogen is added thionyl chloride (2.5 mL, 34.5 mmol) and catalyticamount of DMF, The pressure vessel is sealed and heated to 70° C. whereit is maintained for 2 hours. After this time, the reaction mixture iscooled to room temperature and diluted with dichloromethane and the acidchloride solution is concentrated in vacuo until ˜1 mL left and thisprocess is repeated twice. The crude acid chloride is used withoutfurther purification. The crude acid chloride is diluted with 2 mL oftoluene and added to the vial containing3-[1-(2-Methoxy-ethoxy)-1-methyl-ethyl]-isoxazol-5-ylamine (1 g, 5.0mmol) and N,N-diisopropylethylamine (4.35 mL, 24.98 mmol) in 10 mL oftoluene and the reaction mixture is heated at 55° C. for 18 hours. Afterthis time, the reaction mixture is quenched with saturated sodiumbicarbonate aqueous solution and extracted with ethyl acetate twice. Theorganics are combined and washed with brine, dried over Na₂SO₄, filteredand concentrated under reduced pressure. Purification of the residue byflash chromatography on silica gel using ethyl acetate/heptane providescompound 19 (52%), m/z 350 [M+H⁺]

Compounds listed in intermediate table below are made following thisprocedure with the following modifications to be noted: for LXIIreaction with thionyl chloride is heated at 80° C., for LXIV-LXVreaction with thionyl chloride is heated at 60° C.

TABLE 11 LC Method and Interme- Retention time m/z diate No. StructureYield [%] [min] [M/M + 2H] LIX(com- poun 19)

52 LC Method d: 1.30 349/351 LX

64 LC Method d: 1.49 319/321 [M-THP/M- THP + 2H] LXI

58 LC Method d: 1.52 331/333 [M-THP/M- THP + 2H] LXII

13 LC Method c: 1.28 363/365 LXIII

38 LC Method c: 1.49 317/319 [M-THP/M- THP + 2H] LXIV

31 LC Method c: 1.29 372/374 LXV

32 LC Method c: 1.23 356/358 LXVI

90 LC Method d: 1.25 317/319 [M/M + 2H]

Step 2: Synthesis of Example 36

Sodium hydride in mineral oil (60%, 61.8 mg, 1.55 mmol) is suspended in2 mL of THF and the solution of 4,4,4-Trifluoro-butylamine (81.9 mg,0.64 mmol) in 1 mL of THF is added and the mixture is stirred at roomtemperature for 5 minutes under nitrogen before dropwise adding thesolution of compound 19 (180 mg, 0.52 mmol) in 1.5 mL of THF. Thereaction mixture is stirred at room temperature for 18 hours. After thistime, the reaction mixture is quenched with saturated sodium bicarbonateaqueous solution and extracted with ethyl acetate twice. The organicsare combined and washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification of the residue byflash chromatography on silica gel using ethyl acetate/heptane providesexample 36 (47%), LC-MS (LC Method d): retention time 1.05 min, m/z 396[M+H⁺].

Compounds listed in Table IV under Method L are made following thisprocedure, with the exception of example 14, 31, and 76 for which thelast step is run according to Method B Step 2, and the crude is purifiedby prep HPLC or silica gel chromatography. Further for example 15 inTable IV NaH (4 equivalents) in mineral oil is used.

Also, the following intermediates are made following this procedure,with the exception that for intermediates LXVII-LXXI NaH (4 equivalents)in mineral oil is used.

TABLE 12 LC Method Interme- and Retention time diate No. Structure Yield[%] [min] m/z [M + H] LXVII

27 LC Method d: 1.15 438 LXVIII

42 LC Method d: 1.14 452 LXIX

34 LC Method d: 1.17 464 LXX

16 LC Method d: 1.16 450 LXXI

65 LC Method d: 1.20 450 LXXII

quantitative LC Method d: 1.32 436 LXXIII

61 LC Method c 1.14 448

Method L1

Same as Method C step 3.

Compounds listed in Table IV under Method L1 are made following thisprocedure.

Method M Synthesis of Example 22

Aluminum chloride (188 mg, 1.4 mmol) is added to a cooled (0° C.)suspension of example 91 (33 mg, 0.083 mmol) in ethanethiol (1 mL, 13.5mmol). The reaction mixture is stirred at room temperature for 65 hours.Aluminum chloride (100 mg, 0.74 mmol) is added and the reaction mixtureis stirred at room temperature for 24 hours. After this time, thereaction mixture is quenched with 20 mL of water and 5 drops ofconcentrated hydrochloric acid aqueous solution and the mixture isstirred at room temperature for 1 hour. The mixture is extracted withethyl acetate and the layers are separated. The aqueous layer isbasicified to pH ˜14 by adding 4N sodium hydroxide aqueous solution andthe resulting mixture is extracted with ethyl acetate twice. Theorganics are combined and washed with brine, dried over Na₂SO₄, filteredand concentrated under reduced pressure. Purification of the residue byflash chromatography on silica gel using methanol/methylene chlorideprovides example 22 (88%), m/z 384 [M+H⁺].

Compounds listed in Table IV under Method M are made following thisprocedure.

Method N Synthesis of Example 90

Step 1: Synthesis of Compound 20

To a flask containing compound 1 (11.8 g, 71 mmol) in MeCN (500 mL) isadded EDC.HCl (37.7 g, 212 mmol) and DMAP (8.6 mg, 71 mmol) at roomtemperature. 2-tert-butyl-2H-tetrazol-5-ylamine (10 g, 71 mmol) is addedand the reaction mixture is stirred at room temperature for 24 h. Water(50 mL) is added and extracted with ethyl acetate (3×250 mL). Thecombined organic layers are dried (Na₂SO₄) and the solvent isconcentrated under reduced pressure. The crude material is purified bycolumn chromatography (silica, eluent: heptanes, 0-50% ethyl acetate) toafford 9.4 g of compound 20. Yield: 45%, LC-MS (LC Method b): retentiontime: 1.71 min, m/z 290/292 [M+H].

Step 2: Synthesis of Example 90

N-(cis-4-Aminocyclohexyl)methanesulfonamide (0.22 g, 1.14 mmol) andcompound 20 (0.32 g, 1.14 mmol) are charged into a pressure tube. Thereaction mixture is heated to 150° C. for 20 min until the solids aremelted. After cooling to room temperature, the residue is dissolved inethyl acetate (10 mL) and washed with saturated NaHCO₃ solution (10 mL).The aqueous layer is extracted with ethyl acetate (2×20 mL) and thecombined organic layers are dried over Na₂SO₄ and filtered. The filtrateis concentrated under reduced pressure and the residue is purified bypreparative LC (neutral method) followed by column chromatography(silica, eluent: heptanes, 0-60% ethyl acetate) to afford 6 mg ofexample 90. Yield: 1.3%, LC-MS (LC Method a): retention time: 2.36 min,m/z 402 [M+H].

Synthesis of Compound 25

Step 1: Synthesis of Compound 22

Paratoluenesulfonyl chloride (300.0 g, 1.58 mol) is added to a solutionof compound 21 (100.0 g, 0.98 mol) in 800.0 mL of pyridine at 0° C.After stifling the reaction mixture at room temperature for 14 hours, itis pored into an ice solution of 6N HCl. Some precipitate is formed thatis filtered and triturated with hexanes. After drying under vacuum thecrude compound 22 is used without further purification in the next step.¹H NMR (400 MHz, chloroform-d) δ ppm 1.70-1.89 (4H, m), 2.45 (3H, s),3.44-3.50 (2H, m), 3.86 (2H, p), 4.70 (1H, m), 7.33 (2H, d, 8.4 Hz),7.79 (2H, d, 8.0 Hz).

Step 2: Synthesis of Compound 23

n-BuLi (1.6M solution in hexane, 122.5 mL) is added slowly to a stirredsolution of DIPA in dry THF (150 mL) at −78° C. After stifling thesolution for 1 h at −78° C., Isobutyric acid methyl ester (10.0 g, 98.0mmol) is added slowly and stirred for 3 h at −78° C. Compound 22 (25.1g, 98.0 mmol) is dissolved in THF and added to the reaction mixture thatis stirred for 1 h at −78° C. and 14 h at room temperature. The reactionmixture is quenched with water and extracted with ethyl acetate. Theorganic layer is washed with water and brine, dried over anhy. Na₂SO₄,filtered and concentrated under vacuum. The crude is purified by silicaflash column chromatography (30% Ethyl actetate in heptane), to afford7.0 g of the compound 23 as a pale yellow oil. Yield: 38%.

¹H NMR (400 MHz, chloroform-d) δ ppm 1.13 (6H, s), 1.38-1.45 (4H, m),1.78-1.85 (1H, m), 3.33-3.40 (2H, m), 3.66 (3H, s), 3.98 (2H, dd, 2.8Hz).

Step 3: Synthesis of Compound 24

A solution of compound 23 (6.0 g, 32.2 mmol) in CH₃CN (2.2 mL) is addedto a stirred suspension of NaH (2.1 g, 48.3 mmol) in toluene (60.0 mL)at 80° C. and the reaction mixture is further maintained at refluxtemperature for 14 h. The reaction mixture is cooled to roomtemperature; water is added and extracted with EtOAc (3 times). Theaqueous layer is acidified with 2N aq. HCl solution and extracted withEtOAc. The combined EtOAc layers are washed with brine, dried over anhy.Na₂SO₄, filtered and concentrated under reduced pressure to afford thecompound 24 (4.2 g) that is used in the next step without furtherpurification.

Step 4: Synthesis of Compound 25

Hydroxylamine sulphate (2.95 g, 17.9 mmol) and solid NaOH (2.16 g, 53.77mmol) are added to a stirring solution of compound 24 (3.5 g, 17.9 mmol)in water (35.0 mL), and the resultant reaction mixture is stirred atreflux for 14 h. The reaction mixture is cooled to room temperature andthen extracted with EtOAc (3 times). The combined EtOAc layers arewashed with water, brine, dried over anhy. Na₂SO₄, filtered andconcentrated under reduced pressure. The crude is purified by silica gelcolumn chromatography (50% ethyla cetate in heptane) to afford 1.4 g ofcompound 25. Yield: 37%, LC-MS (Method d): retention time: 1.09 min, m/z211 [M+H].

Synthesis of Compound 28

A solution of compound 26 and compound 27 in conc. HCl is heated at 100°C. for 3 h. The reaction mixture is quenched with aq NH₃ solution andextracted with ethyl acetate (twice). The combined EtOAc fraction iswashed with brine solution, dried over anh. Na₂SO₄, filtered andconcentrated under reduced pressure. The crude is purified by silica gelcolumn chromatography (5% methanol in dichloromethane) to afford 0.85 gof compound 28. Yield: 30%, LC-MS (Method d): retention time: 0.74 min,m/z 186 [M+H].

Method O Synthesis of Example 58

A microwave reaction vessel is charged with a solution of compound 29(120 mg, 0.37 mmol, prepared according to WO2009105509, BoehringerIngelheim) in THF (2 mL) and NaH (60% dispersion in mineral oil, 15 mg,0.37 mmol) is added. The mixture is stirred at room temperature for 5min and methanesulfonylchloride (28 μL, 0.37 mmol) is added. Thereaction mixture is heated in a microwave to 70° C. for 1 h. The mixtureis diluted with ethyl acetate (20 mL) and washed with 1N aqueous HClsolution (2×3 mL) and brine (3 mL). The organic layer is dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue isdissolved in ethyl acetate and heptanes are added. The resulting whiteprecipitate is isolated by filtration and dried under reduced pressureto afford 18 mg of example 58. Yield: 12%; LC-MS (Method a): retentiontime: 3.92 min, m/z 402 [M+H].

Compounds listed in Table IV under Method O are made following thisprocedure.

TABLE IV Examples retention Example LC time m/z # Structure Method [min][M + H+] Method 1

a 2.40 340 A 2

a 2.16 326 B 3

a 2.17 340 C 4

a 2.19 310 C 5

a 2.56 338 C 6

a 2.35 324 D 7

c 0.71 354 C 8

f 0.82 298 C 9

c 0.50 403 C 10

a 2.14 326 E 11

a 2.60 354 A 12

a 2.50 340 A 13

a 2.25 340 E 14

g 4.00 429 L 15

c 0.92 398 L 16

d 0.86 354 L1 17

f 0.94 368 L1 18

d 0.97 380 L1 19

d 0.93 366 L1 20

c 0.33 352 L1 21

d 1.08 384 L 22

d 0.90 384 M 23

g 3.96 406 J 24

g 3.40 469 K 25

d 0.77 338 J 26

d 1.04 408 J 27

c 0.97 412 J 28

d 0.73 340 J 29

c 0.77 366 J1 30

c 0.40 371 J2 31

g 4.03 391.7 L 32

g 4.19 405 J 33

g 4.28 468 K 34

d 0.98 366 L1 35

d 0.83 370 M 36

d 1.05 396 L 37

c 0.74 398 M 38

d 1.03 394 K 39

d 0.94 382 M 40

c 0.85 364 L1 41

a 2.89 424 C 42

a 2.14 340 C 43

a 2.36 340 C 44

a 2.74 410 C 45

a 1.87 326 C 46

a 2.60 368 F 47

a 2.25 417 C 48

a 2.51 352 C 49

a 2.33 324 C 50

a 3.06 382 G 51

a 2.30 354 C 52

a 2.19 354 H 53

a 1.86 312 C 54

a 2.35 312 I 55

a 2.24 310 I 56

a 2.18 296 C 57

a 2.13 340 C 58

a 3.92 402 O 59

a 2.19 417 C 60

a 2.42 354 C 61

a 2.09 403 C 62

a 2.48 431 I 63

a 2.08 340 C 64

a 2.41 310 C 65

a 2.90 368 G 66

a 2.26 296 C 67

a 2.49 431 I 68

a 2.38 338 C 69

c 0.96 407 J 70

c 0.52 357 J2 71

c 0.97 419 L 72

c 0.92 403 L 73

f 0.85 401 K1 74

c 0.54 384 M 75

g 4.05 403 K1 76

g 4.34 468 L 77

g 4.22 484 K 78

c 0.84 350 L 79

c 1.09 405 L 80

c 1.02 389 L 81

c 1.01 421 J 82

a 3.09 368 G 83

a 3.51 380 G 84

a 2.90 403 I 85

a 2.86 403 I 86

a 2.36 356 C 87

a 2.38 3.56 C 88

a 3.66 394 G 89

a 3.51 352 G 90

a 2.36 402 N 91

d 0.96 398 LAnalytical MethodsLC Method a:

-   HPLC-MS Equipment-   HPLC pumps: Agilent G1312A-   Autoinjectors: CTC PAL HTC-   Detectors:    -   MS: Waters ZQ    -   UV: Waters 2996 photodiode array    -   Ancillary: Waters 2420 evaporative light scattering detectors        (ELS)

Higher specification method designed for medicinal chemistry samplescreening Column Waters Atlantis dC18 Flow rate 0.6 ml/min 2.1 × 100 mm,3 μm column Mobile Phase A, 0.1% Formic acid (water) Injection Vol 3 μlB, 0.1% Formic acid (CH₃CN) Temp. 40° C. Detection 215 nm (nominal)Gradient Time (mins) % organic 0.00 5 See FIG. ½ 5.00 100 5.40 100 5.425 7.00 5LC Method b:

-   HPLC-MS equipment:-   Shimadzu LCMS-2010EV system: (MS, pump, PDA)-   Autoinjectors CTC PAL HTS autosampler

Standard method for routine high throughput analysis Column AtlantisdC18 Flow rate 1 ml/min 2.1 × 50 mm, 5 μm Mobile Phase A, Formic acid(aq) 0.1% Injection Vol 3 μl B, Formic acid (CH₃CN) 0.1% Temp. 40° C.Detection 215 nm (nominal) Gradient Time (mins) % organic 0.00 5 See.FIG. 2/2 2.50 100 2.70 100 2.71 5 3.00 5

LC Method c: Column: Agilent SB-C18 1.81 μm 3 × 50 mm, 1.5 mL/min flowrate Time Water Acetonitrile (min) (0.1% FA) (0.1% FA) 0 88 12 0.25 7030 0.3 60 40 1.19 5 95 1.75 0 100

LC Method d: Column: Agilent SB-AQ 1.81 μm 3 × 50 mm, 1.5 mL/min flowrate Time Water Acetonitrile (min) (0.1% FA) (0.1% FA) 0 95 5 0.25 50 500.3 30 70 1.3 10 90 1.7 0 100

LC Method e: Column: BEH C18, 1.7 μm 2.1 × 50 mm, 0.8 mL/min flow rateTime Water Acetonitrile (min) (0.05% FA) (0.05% FA) 0 90 10 1.19 5 951.7 5 95

LC Method f: Column: Agilent Zorbax C18 SB 3.5 μm 4.6 × 30 mm, 2.5mL/min flow rate Time Water Acetonitrile (min) (0.1% FA) (0.1% FA) 0 955 1.7 5 95 2.0 5 95 2.1 95 5 2.3 95 5

LC Method g: Column: Agilent Zorbax Eclipse XDB-C8 5.0 μm 4.6 × 150 mm,1.5 mL/min flow rate Time Water Acetonitrile (min) (0.1% FA) (0.1% FA) 095 5 2.0 95 5 7.0 10 90 9.0 5 95 9.3 95 5 10.0 95 5

LC Method h: Column: Zorbax XDB-C8 4.6 × 50 mm 3.5 μm, 2 mL/min flowrate Time Water Acetonitrile (min) (0.05% FA) (0.05% FA) 0.0 95 5 3.5 4060 4.5 5 95 4.7 95 5 5.0 95 5Assessment of Biological Properties

The biological properties of the compounds of the formula I are assessedusing the assays described below.

A. Human CB1 and CB2 Receptor Binding:

Experimental Method:

CB2 membranes are purchased and made from HEK293 EBNA cells stablytransfected with human CB2 receptor cDNA (Perkin Elmer Life andAnalytical Sciences). CB1 membranes are isolated from HEK cells stablyco-transfected with human CB1 receptor and Gα16 cDNA's. The membranepreparation is bound to scintillation beads (Ysi-Poly-L-lysine SPAbeads, GE Healthcare) for 4 hours at room temperature in assay buffercontaining 50 mM Tris, pH 7.5, 2.5 mM EDTA, 5 mM MgCl₂, 0.8% fatty acidfree Bovine Serum Albumin. Unbound membrane is removed by washing inassay buffer. Membrane-bead mixture is added to 96-well assay plates inthe amounts of 15 ug membrane per well (CB2) or 2.5 ug per well (CB1)and 1 mg SPA bead per well. Compounds are added to the membrane-beadmixture in dose-response concentrations ranging from 1×10⁻⁵M to 1×10⁻¹⁰M with 0.25% DMSO, final. The competition reaction is initiated with theaddition of ³H-CP55940 (Perkin Elmer Life and Analytical Sciences) at afinal concentration of 1.5 nM (CB2) or 2.5 nM (CB1). The reaction isincubated at room temperature for 18 hours and read on TopCount NXTplate reader. Total and non-specific binding is determined in theabsence and presence of 1.25 uM Win 55212 (Sigma). IC50 values for eachcompound are calculated as the concentration of compound that inhibitsthe specific binding of the radioactively labeled ligand to the receptorby 50% using the XLFit 4.1 four parameter logistic model. IC50 valuesare converted to inhibition constant (Ki) values using Cheng-Prusoffequation.

B. CB2R Mediated Modulation of cAMP Synthesis:

Compounds of the invention are evaluated for their CB2 agonist orinverse agonistic activity in accordance with the following experimentalmethod. Compounds which are shown to bind to CB2 by the binding assaydescribed above but which are not shown to exhibit CB2R-mediatedmodulation of cAMP synthesis by this assay are presumed to be CB2antagonists.

Experimental Method:

CHO cells expressing human CB2R (Euroscreen) are plated at a density of5000 cells per well in 384 well plates and incubated overnight at 37° C.After removing the media, the cells are treated with test compoundsdiluted in stimulation buffer containing 1 mM IBMX, 0.25% BSA and 10 uMForskolin. The assay is incubated for 30 minutes at 37° C. Cells arelysed and the cAMP concentration is measured using DiscoverX-XS cAMPkit, following the manufacturer's protocol. In this setting, agonistswill decrease forskolin induced production of cAMP while inverseagonists will further increase forskolin induced production of cAMP.EC50 of agonists are calculated as follows. The maximal amount of cAMPproduced by forskolin compared to the level of cAMP inhibited by 1 uMCP55940 is defined as 100%. The EC50 value of each test compound isdetermined as the concentration at which 50% of the forskolin-stimulatedcAMP synthesis is inhibited. Data is analyzed using a four-parameterlogistic model. (Model 205 of XLfit 4.0).

C. CB1R Mediated Modulation of cAMP Synthesis:

Compounds of the invention are evaluated for their CB1 agonist orinverse agonistic activity in accordance with the following experimentalmethod. Compounds which are shown to bind to CB1 by the binding assaydescribed above but which are not shown to exhibit CB1R-mediatedmodulation of cAMP synthesis by this assay are presumed to be CB1antagonists.

Experimental Method:

CHO cells expressing human CB1R (Euroscreen) are plated at a density of5000 cells per well in 384 well plates and incubated overnight at 37° C.After removing the media, the cells are treated with test compoundsdiluted in stimulation buffer containing 1 mM IBMX, 0.25% BSA and 10 uMForskolin. The assay is incubated for 30 minutes at 37° C. Cells arelysed and the cAMP concentration is measured using DiscoverX-XS cAMPkit, following the manufacturer's protocol. In this setting, agonistswill decrease forskolin induced production of cAMP while inverseagonists will further increase forskolin induced production of cAMP.EC50 of agonists are calculated as follows. The maximal amount of cAMPproduced by forskolin compared to the level of cAMP inhibited by 1 uMCP55940 is defined as 100%. The EC50 value of each test compound isdetermined as the concentration at which 50% of the forskolin-stimulatedcAMP synthesis is inhibited. Data is analyzed using a four-parameterlogistic model. (Model 205 of XLfit 4.0).

Compounds Having Agonist Activity

Through the use of the above described assays compounds are found toexhibit agonistic activity and thus to be particularly well suited forthe treatment of pain as well as for the treatment of inflammation.Preferred compounds of the invention will have an activity range of CB2(<500 nM) and CB1 (>20000).

Therapeutic Use

As can be demonstrated by the assays described above, the compounds ofthe invention are useful in modulating the CB2 receptor function. Byvirtue of this fact, these compounds have therapeutic use in treatingdisease-states and conditions mediated by the CB2 receptor function orthat would benefit from modulation of the CB2 receptor function.

As the compounds of the invention modulate the CB2 receptor function,they have very useful anti-inflammatory and immune-suppressive activityand they can be used in patients as drugs, particularly in the form ofpharmaceutical compositions as set forth below, for the treatment ofdisease-states and conditions.

As noted before, those compounds which are CB2 agonists can also beemployed for the treatment of pain.

The agonist, antagonist and inverse agonist compounds according to theinvention can be used in patients as drugs for the treatment of thefollowing disease-states or indications that are accompanied byinflammatory processes:

-   -   (i) Lung diseases: e.g. asthma, bronchitis, allergic rhinitis,        emphysema, adult respiratory distress syndrome (ARDS), pigeon        fancier's disease, farmer's lung, chronic obstructive pulmonary        disease (COPD), asthma including allergic asthma (atopic or        non-atopic) as well as exercise-induced bronchoconstriction,        occupational asthma, viral- or bacterial exacerbation of asthma,        other non-allergic asthmas and “wheezy-infant syndrome”,        pneumoconiosis, including aluminosis, anthracosis, asbestosis,        chalicosis, ptilosis, siderosis, silicosis, tabacosis and        byssinosis;    -   (ii) Rheumatic diseases or autoimmune diseases or        musculoskeletal diseases: all forms of rheumatic diseases,        especially rheumatoid arthritis, acute rheumatic fever, and        polymyalgia rheumatica; reactive arthritis; rheumatic soft        tissue diseases; inflammatory soft tissue diseases of other        genesis; arthritic symptoms in degenerative joint diseases        (arthroses); tendinitis, bursitis, osteoarthritis, traumatic        arthritis; collagenoses of any genesis, e.g., systemic lupus        erythematosus, scleroderma, polymyositis, dermatomyositis,        Sjögren syndrome, Still disease, Felty syndrome; and        osteoporosis and other bone resorption diseases;    -   (iii) Allergic diseases: all forms of allergic reactions, e.g.,        angioneurotic edema, hay fever, insect bites, allergic reactions        to drugs, blood derivatives, contrast agents, etc., anaphylactic        shock (anaphylaxis), urticaria, angioneurotic edema, and contact        dermatitis;    -   (iv) Vascular diseases: panarteritis nodosa, polyarteritis        nodosa, periarteritis nodosa, arteritis temporalis, Wegner        granulomatosis, giant cell arthritis, atherosclerosis,        reperfusion injury and erythema nodosum;    -   (v) Dermatological diseases: e.g. dermatitis, psoriasis;        sunburn, burns, eczema;    -   (vi) Renal diseases: e.g. nephrotic syndrome; and all types of        nephritis, e.g., glomerulonephritis; pancreatits;    -   (vii) Hepatic diseases: e.g. acute liver cell disintegration;        acute hepatitis of various genesis, e.g., viral, toxic,        drug-induced; and chronically aggressive and/or chronically        intermittent hepatitis;    -   (viii) Gastrointestinal diseases: e.g. inflammatory bowel        diseases, irritable bowel syndrome, regional enteritis (Crohns        disease), colitis ulcerosa; gastritis; aphthous ulcer, celiac        disease, regional ileitis, gastroesophageal reflux disease;    -   (ix) Neuroprotection: e.g. in the treatment of neurodegeneration        following stroke; cardiac arrest; pulmonary bypass; traumatic        brain injury; spinal cord injury or the like;    -   (x) Eye diseases: allergic keratitis, uveitis, or iritis;        conjunctivitis; blepharitis; neuritis nervi optici; choroiditis;        glaucoma and sympathetic ophthalmia;    -   (xi) Diseases of the ear, nose, and throat (ENT) area: e.g.        tinnitus; allergic rhinitis or hay fever; otitis externa; caused        by contact eczema, infection, etc.; and otitis media;    -   (xii) Neurological diseases: e.g. brain edema, particularly        tumor-related brain edema; multiple sclerosis; acute        encephalomyelitis; meningitis; acute spinal cord injury; trauma;        dementia, particularly degenerative dementia (including senile        dementia, Alzheimer's disease; Parkinson's disease and        Creutzfeldt-Jacob disease; Huntington's chorea, Pick's disease;        motor neuron disease), vascular dementia (including        multi-infarct dementia) as well as dementia associated with        intracranial space occupying lesions; infections and related        conditions (including HIV infection); Guillain-Barre syndrome;        myasthenia gravis, stroke; and various forms of seizures, e.g.,        nodding spasms;    -   (xiii) Blood diseases: acquired hemolytic anemia; aplastic        anemia, and idiopathic thrombocytopenia;    -   (xiv) Tumor diseases: acute lymphatic leukemia; Hodgkin's        disease, malignant lymphoma; lymphogranulomatoses;        lymphosarcoma; solid malignant tumors; extensive metastases;    -   (xv) Endocrine diseases: endocrine ophthalmopathy; endocrine        orbitopathia; thyrotoxic crisis; Thyroiditis de Quervain;        Hashimoto thyroiditis; Morbus Basedow; granulomatous        thyroiditis; struma lymphomatosa; and Graves disease; type I        diabetes (insulin-dependent diabetes);    -   (xvi) Organ and tissue transplantations and graft-versus-host        diseases;    -   (xvii) Severe states of shock, e.g., septic shock, anaphylactic        shock, and systemic inflammatory response syndrome (SIRS);    -   (xviii) Acute pain such as dental pain, perioperative,        post-operative pain, traumatic pain, muscle pain, pain in burned        skin, sun burn, trigeminal neuralgia, sun burn; spasm of the        gastrointestinal tract or uterus, colics;    -   (xix) Visceral pain such as pain associated with chronic pelvic        pain, pancreatitis, peptic ulcer, interstitial cystitis, renal        colic, angina, dysmenorrhoea, menstruation, gynaecological pain,        irritable bowel syndrome (IBS), non-ulcer dyspepsia, non-cardiac        chest pain, myocardial ischemia;    -   (xx) Neuropathic pain such as low back pain, non-herpetic        neuralgia, post herpetic neuralgia, diabetic neuropathy, nerve        injury, acquired immune deficiency syndrome (AIDS) related        neuropathic pain, head trauma, painful traumatic mononeuropathy,        toxin and chemotherapy induced pain, phantom limb pain, painful        polyneuropathy, thalamic pain syndrome, post-stroke pain,        central nervous system injury, post surgical pain, stump pain,        repetitive motion pain, pain induced by post mastectomy        syndrome, multiple sclerosis, root avulsions, postthoracotomy        syndrome, neuropathic pain associated hyperalgesia and        allodynia.    -   (xxi) Inflammatory/nociceptive pain induced by or associated        with disorders such as osteoarthritis, rheumatoid arthritis,        rheumatic disease, teno-synovitis, gout, vulvodynia, myofascial        pain (muscular injury, fibromyalgia), tendonitis,        osteoarthritis, juvenile arthritis, spondylitis, gouty        arthritis, psoriatic arthritis, muscoskeletal pain,        fibromyalgia, sprains and strains, sympathetically maintained        pain, myositis, pain associated with migraine, toothache,        influenza and other viral infections such as the common cold,        rheumatic fever, systemic lupus erythematosus;    -   (xxii) Cancer pain induced by or associated with tumors such as        lymphatic leukemia; Hodgkin's disease, malignant lymphoma;        lymphogranulomatoses; lympho sarcoma; solid malignant tumors;        extensive metastases;    -   (xxiii) Headache such as cluster headache, migraine with and        without aura, tension type headache, headache with different        origins, headache disorders including prophylactic and acute        use;    -   (xxiv) various other disease-states or conditions including,        restenosis following percutaneous transluminal coronary        angioplasty, acute and chronic pain, atherosclerosis,        reperfusion injury, congestive heart failure, myocardial        infarction, thermal injury, multiple organ injury secondary to        trauma, necrotizing enterocolitis and syndromes associated with        hemodialysis, leukopheresis, and granulocyte transfusion,        sarcoidosis, gingivitis, pyrexia. edema resulting from trauma        associated with bums, sprains or fracture, cerebral oedema and        angioedema, Diabetes such as diabetic vasculopathy, diabetic        neuropathy, diabetic retinopathy, post capillary resistance or        diabetic symptoms associated with insulitis (e.g. hyperglycemia,        diuresis, proteinuria and increased nitrite and kallikrein        urinary excretion).

Other indications include: epilepsy, septic shock e.g. asantihypovolemic and/or antihypotensive agents, cancer, sepsis,osteoporosis, benign prostatic hyperplasia and hyperactive bladder,pruritis, vitiligo, general gastrointestinal disorders, disturbances ofvisceral motility at respiratory, genitourinary, gastrointestinal orvascular regions, wounds, burns, tissue damage and postoperative fever,syndromes associated with Itching.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like.

For treatment of the above-described diseases and conditions, atherapeutically effective dose will generally be in the range from about0.01 mg to about 100 mg/kg of body weight per dosage of a compound ofthe invention; preferably, from about 0.1 mg to about 20 mg/kg of bodyweight per dosage. For example, for administration to a 70 kg person,the dosage range would be from about 0.7 mg to about 7000 mg per dosageof a compound of the invention, preferably from about 7.0 mg to about1400 mg per dosage. Some degree of routine dose optimization may berequired to determine an optimal dosing level and pattern. The activeingredient may be administered from 1 to 6 times a day.

General Administration and Pharmaceutical Compositions

When used as pharmaceuticals, the compounds of the invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared using procedures well known in thepharmaceutical art and comprise at least one compound of the invention.The compounds of the invention may also be administered alone or incombination with adjuvants that enhance stability of the compounds ofthe invention, facilitate administration of pharmaceutical compositionscontaining them in certain embodiments, provide increased dissolution ordispersion, increased inhibitory activity, provide adjunct therapy, andthe like. The compounds according to the invention may be used on theirown or in conjunction with other active substances according to theinvention, optionally also in conjunction with other pharmacologicallyactive substances. In general, the compounds of this invention areadministered in a therapeutically or pharmaceutically effective amount,but may be administered in lower amounts for diagnostic or otherpurposes.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using any ofthe accepted modes of administration of pharmaceutical compositions.Thus, administration can be, for example, orally, buccally (e.g.,sublingually), nasally, parenterally, topically, transdermally,vaginally, or rectally, in the form of solid, semi-solid, lyophilizedpowder, or liquid dosage forms, such as, for example, tablets,suppositories, pills, soft elastic and hard gelatin capsules, powders,solutions, suspensions, or aerosols, or the like, preferably in unitdosage forms suitable for simple administration of precise dosages. Thepharmaceutical compositions will generally include a conventionalpharmaceutical carrier or excipient and a compound of the invention asthe/an active agent, and, in addition, may include other medicinalagents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles,or combinations thereof. Such pharmaceutically acceptable excipients,carriers, or additives as well as methods of making pharmaceuticalcompositions for various modes or administration are well-known to thoseof skill in the art. The state of the art is evidenced, e.g., byRemington: The Science and Practice of Pharmacy, 20th Edition, A.Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook ofPharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995;Handbook of Pharmaceutical Excipients, A. H. Kibbe (ed.), AmericanPharmaceutical As s′ n, 2000; H. C. Ansel and N. G. Popovish,Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea andFebiger, 1990; each of which is incorporated herein by reference intheir entireties to better describe the state of the art.

As one of skill in the art would expect, the forms of the compounds ofthe invention utilized in a particular pharmaceutical formulation willbe selected (e.g., salts) that possess suitable physical characteristics(e.g., water solubility) that is required for the formulation to beefficacious.

Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of the presentinvention in a flavored base, usually sucrose, and acacia or tragacanth,and pastilles comprising the compound in an inert base such as gelatinand glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administrationcomprise sterile aqueous preparations of a compound of the presentinvention. These preparations are preferably administered intravenously,although administration can also be effected by means of subcutaneous,intramuscular, or intradermal injection. Injectable pharmaceuticalformulations are commonly based upon injectable sterile saline,phosphate-buffered saline, oleaginous suspensions, or other injectablecarriers known in the art and are generally rendered sterile andisotonic with the blood. The injectable pharmaceutical formulations maytherefore be provided as a sterile injectable solution or suspension ina nontoxic parenterally acceptable diluent or solvent, including1,3-butanediol, water, Ringer's solution, isotonic sodium chloridesolution, fixed oils such as synthetic mono- or diglycerides, fattyacids such as oleic acid, and the like. Such injectable pharmaceuticalformulations are formulated according to the known art using suitabledispersing or setting agents and suspending agents. Injectablecompositions will generally contain from 0.1 to 5% w/w of a compound ofthe invention.

Solid dosage forms for oral administration of the compounds includecapsules, tablets, pills, powders, and granules. For such oraladministration, a pharmaceutically acceptable composition containing acompound(s) of the invention is formed by the incorporation of any ofthe normally employed excipients, such as, for example, pharmaceuticalgrades of mannitol, lactose, starch, pregelatinized starch, magnesiumstearate, sodium saccharine, talcum, cellulose ether derivatives,glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Suchsolid pharmaceutical formulations may include formulations, as arewell-known in the art, to provide prolonged or sustained delivery of thedrug to the gastrointestinal tract by any number of mechanisms, whichinclude, but are not limited to, pH sensitive release from the dosageform based on the changing pH of the small intestine, slow erosion of atablet or capsule, retention in the stomach based on the physicalproperties of the formulation, bioadhesion of the dosage form to themucosal lining of the intestinal tract, or enzymatic release of theactive drug from the dosage form.

Liquid dosage forms for oral administration of the compounds includeemulsions, microemulsions, solutions, suspensions, syrups, and elixirs,optionally containing pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike. These compositions can also contain additional adjuvants such aswetting, emulsifying, suspending, sweetening, flavoring, and perfumingagents.

Topical dosage forms of the compounds include ointments, pastes, creams,lotions, gels, powders, solutions, sprays, inhalants, eye ointments, eyeor ear drops, impregnated dressings and aerosols, and may containappropriate conventional additives such as preservatives, solvents toassist drug penetration and emollients in ointments and creams. Topicalapplication may be once or more than once per day depending upon theusual medical considerations. Furthermore, preferred compounds for thepresent invention can be administered in intranasal form via topical useof suitable intranasal vehicles. The formulations may also containcompatible conventional carriers, such as cream or ointment bases andethanol or oleyl alcohol for lotions. Such carriers may be present asfrom about 1% up to about 98% of the formulation, more usually they willform up to about 80% of the formulation.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal administration can be presented as discretepatches adapted to remain in intimate contact with the epidermis of therecipient for a prolonged period of time. To be administered in the formof a transdermal delivery system, the dosage administration will, ofcourse, be continuous rather than intermittent throughout the dosageregimen. Such patches suitably contain a compound of the invention in anoptionally buffered, aqueous solution, dissolved and/or dispersed in anadhesive, or dispersed in a polymer. A suitable concentration of theactive compound is about 1% to 35%, preferably about 3% to 15%.

For administration by inhalation, the compounds of the invention areconveniently delivered in the form of an aerosol spray from a pump spraydevice not requiring a propellant gas or from a pressurized pack or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbondioxide, or other suitable gas. In any case, the aerosol spray dosageunit may be determined by providing a valve to deliver a metered amountso that the resulting metered dose inhaler (MDI) is used to administerthe compounds of the invention in a reproducible and controlled way.Such inhaler, nebulizer, or atomizer devices are known in the prior art,for example, in PCT International Publication Nos. WO 97/12687(particularly FIG. 6 thereof, which is the basis for the commercialRESPIMAT® nebulizer); WO 94/07607; WO 97/12683; and WO 97/20590, towhich reference is hereby made and each of which is incorporated hereinby reference in their entireties.

Rectal administration can be effected utilizing unit dose suppositoriesin which the compound is admixed with low-melting water-soluble orinsoluble solids such as fats, cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights, or fatty acid esters of polyethylene glycols, or thelike. The active compound is usually a minor component, often from about0.05 to 10% by weight, with the remainder being the base component.

In all of the above pharmaceutical compositions, the compounds of theinvention are formulated with an acceptable carrier or excipient. Thecarriers or excipients used must, of course, be acceptable in the senseof being compatible with the other ingredients of the composition andmust not be deleterious to the patient. The carrier or excipient can bea solid or a liquid, or both, and is preferably formulated with thecompound of the invention as a unit-dose composition, for example, atablet, which can contain from 0.05% to 95% by weight of the activecompound. Such carriers or excipients include inert fillers or diluents,binders, lubricants, disintegrating agents, solution retardants,resorption accelerators, absorption agents, and coloring agents.Suitable binders include starch, gelatin, natural sugars such as glucoseor β-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride, and the like. Disintegrators include starch,methyl cellulose, agar, bentonite, xanthan gum, and the like.

Pharmaceutically acceptable carriers and excipients encompass all theforegoing additives and the like.

1. A compound of the formula (I)

wherein: ring A is a 5-membered heteroaryl ring; R¹ is hydrogen, C₁₋₁₀alkyl or C₃₋₁₀ cycloalkyl which is optionally substituted with 1-3 C₁₋₁₀alkyl, each R¹ or it's substituent is optionally halogenated; R² ismethyl substituted with 1 heterocyclyl, each substituent on R² wherepossible is optionally halogenated or substituted with 1 to 3 C₁₋₆alkyl, C₁₋₆ acyl, C₁₋₆ alkyl sulfonyl, cyano, aryl, oxo or hydroxyl; R³and R³′ are independently hydrogen or C₁₋₆ alkyl optionally halogenatedwith the proviso that R³ and R³′ cannot simultaneously be hydrogen; R⁴is hydrogen or methyl; R⁵ is chosen from

m is 0, 1, 2 or 3; R⁶ is hydrogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; R⁷ and R⁸are each independently hydrogen, or C₁₋₄ alkyl with the proviso thatboth R⁷ and R⁸ cannot be hydrogen; and wherein R⁷ and R⁸ optionally cancyclize to form a C₃₋₇ cycloalkyl ring; R⁹ is C₁₋₆ alkyl or aryl; ring Bis a 5-6 membered heterocyclic ring; n is 0, 1 or 2; wherein any carbonatom on the formula (I) or any R substituent listed above is optionallypartially or fully halogenated where possible; or a pharmaceuticallyacceptable salt thereof.
 2. The compound according to claim 1 andwherein ring A is

R² is methyl substituted with 1 heterocyclyl chosen fromtetrahydropyranyl, dioxanyl, tetrahydrofuranyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyrrolidinyl, piperidinyland piperazinyl, each R² substituent where possible is optionallyhalogenated or substituted with 1 to 3 C₁₋₅ alkyl, C₁₋₅ acyl, methylsulfonyl, cyano, phenyl, oxo or hydroxyl; R³ and R³′ are each methyl orethyl, each optionally halogenated.
 3. The compound according to claim 2and wherein ring A is

R¹ is hydrogen or C₁₋₃ alkyl optionally halogenated; R² is methylsubstituted with 1 heterocyclyl chosen from tetrahydropyranyl, dioxanyl,tetrahydrofuranyl, thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholinyl,morpholinyl, pyrrolidinyl, piperidinyl and piperazinyl each optionallyhalogenated or substituted with C₁₋₄ alkyl or methyl sulfonyl; R³ andR³′ are each methyl or ethyl; R⁶ is hydrogen or C₁₋₂ alkyl; R⁷ and R⁸are each C₁₋₂ alkyl.
 4. The compound according to claim 3 and whereinring A is

R² is methyl optionally substituted with one heterocyclyl chosen fromtetrahydropyranyl, dioxanyl, tetrahydrofuranyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyrrolidinyl, piperidinyland piperazinyl each optionally halogenated or substituted with C₁₋₄alkyl or methyl sulfonyl.
 5. The compound according to claim 3, andwherein ring A is

R³ and R³′ are methyl; R⁶ is hydrogen or C₁₋₂ alkyl; wherein R⁷ and R⁸are each C₁₋₂ alkyl.
 6. The compound according to claim 5, and whereinring A is


7. The compound according to claim 6 and wherein ring A is


8. The compound according to claim 2, and wherein R² istetrahydrofuranyl-CH₂—; ring A is

R⁵ is

wherein wherein R⁷ and R⁸ optionally can cyclize to form a C₃₋₇cycloalkyl ring.
 9. The compound according to claim 2, and wherein ringA is

R⁵ is

wherein wherein R⁷ and R⁸ optionally can cyclize to form a C₃₋₇cycloalkyl ring.
 10. A compound of the formula (I) wherein thedefintions: ring A, R¹, R², R³, R³′, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, m, ring B,and n are as defined in claim 1 and wherein R⁷ and R⁶ can cyclize toform a 4-6 membered heterocyclic ring.
 11. A compound of the formula(II)

wherein

of the formula (II) is chosen from column A1-A8 in the table, and

of the formula (II) is chosen from column B1-B19 in the table,

A1

B1

A2

B2

A3

B3

A4

B4

A5

B5

A6

B6

A7

B7

A8

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

or a pharmaceutically acceptable salt thereof.
 12. A compound chosenfrom

or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1 or 12 and one or more pharmaceutically acceptablecarriers and/or adjuvants.
 14. A method of treating pain comprisingadministering a therapeutically effective amount of a compound accordingto claim 1 or
 12. 15. The method according to claim 14 wherein pain ischosen from acute pain, visceral pain, neuropathic pain, inflammatoryand nociceptive pain, cancer pain and headache.